One-pot , four-component synthesis of pyrano [ 2 , 3c ] pyrazoles catalyzed by sodium benzoate in aqueous medium

Article history: Received March 20, 2013 Received in Revised form July 7, 2013 Accepted 10 July 2013 Available online 12 July 2013 An efficient, green, and facile four-component reaction for the preparation of pyrano[2,3c]pyrazole derivatives through the condensation reaction of aryl aldehydes, ethyl acetoacetate, malononitrile, and hydrazine hydrate or phenyl hydrazine in the presence of commercially available organocatalyst sodium benzoate under aqueous condition is reported. The products are produced with high yields and in shorter reaction times. It also is mild, safe, green and environmental friendly. © 2013 Growing Science Ltd. All rights reserved.

][40][41][42][43] Sodium benzoate is a readily accessible commercially material, and has been used in cosmetics and pharmaceutical industry.This compound is also well known for their application in food industry as a safe preservative and antimicrobial agent.Literature survey also reveals that sodium benzoate has been employed as an eco-friendly base catalyst for the synthesis of cyclic ketones, 44 arylmethylene isoxazol-5(4H)-ones, 45 and substituted olefins via Knoevenagel condensation. 46 consideration of green chemical methodology, here we report the synthesis of pyranopyrazoles (5) starting from aryl aldehydes (1), hydrazines (2), ethyl acetoacetate (3), and malononitrile (4) using sodium benzoate as the mild basic catalyst in water (Scheme 1).

Results and Discussion
As an introductory test, we run a model reaction by stirring an equimolecular amounts of 4hydroxybenzaldehyde (1g) with hydrazine hydrate (2a), ethyl acetoacetate (EAA) (3), and malononitrile (4) in the presence of sodium benzoate (2.5 mol %) in water (5 mL) at 25 °C that result in the formation of the desired compound 5g with 45% yield (Table 1, entry 1).The product was identified by spectral data and mixed melting point with an authentic sample.In order to seek an optimal solvent and optimal amounts of catalyst, the model reaction was explored using different solvents such as water, ethanol, tetrahydrofuran (THF), dichloromethane, chloroform, and mixture of water/ethanol (1:1) at room temperature (Table 1, entries 6-10).Also, in order to optimize the sodium benzoate loading, the model reaction was performed with different amounts of catalyst at ambient temperature.The results are summarized in Table 1.It was found that polarity of solvent and presence of sodium benzoate play an important role for the success of the reaction.The results indicated that solvents were also affected on the yield of 5g (Table 1, entries 4-8).In the organic solvents such as dichloromethane, THF, ethanol, or chloroform, the yield of 5g were lower and longer reaction times were required, whereas the reaction using water resulted in good yields (Table 1, entries 1-4).Based on the results, water was chosen to be the best in terms of the yield of the product and reaction time in comparison to common organic solvents.From Table 1, we observed that the yield of product 5g was improved and the reaction time was relatively shortened when the amount of catalyst was increased from 2.5 mol% to 15 mol% (Table 1, entries 1-4).
After optimization the reaction conditions, the scope of the method was investigated with a series of substituted aromatic aldehydes and phenyl hydrazine.The results are summarized in Table 2.As seen from Table 2, the aromatic aldehydes carrying both electron-withdrawing (Entries 2-4, 9-10, 12-13 and 17) and electron-donating functional groups (Entries 5-8 and 14-16) underwent successful condensation with hydrazine hydrate, EAA, and malononitrile in the presence of catalytic amount of sodium benzoate in water at room temperature to afford the corresponding products in good yields.It seems that the electronic effects and the nature of the substituents on the aryl aldehyde ring have slight effect on both reaction yield and necessary time for the completion of the reaction.The electron-donating groups somewhat increased reactivity and afforded higher yields compared to electron-withdrawing groups.In addition, this reaction was affected by steric effect.For example, 2nitrobenzaldehyd (1d) required longer reaction time compared to 4-nitrobenzaldeyde (1b) owing to sterically hindered ortho position, substituted by nitro group 1d.However, when the reaction of phenyl hydrazine was carried out with aryl aldehydes, EAA, and malononitrile, corresponding products were obtained in good yields after longer reaction times, compared to hydrazine hydrate (Table 2, entries 11-17).In this case, the effects of functional groups in the aromatic aldehyde ring were opposite.Remarkably, the reactions were clean and all the products were obtained after only a filtration and simple washing with water and ethanol.Thus, a simple work-up gives the title products without of need of chromatographic purification.a Reagents and conditions: aryl aldehyde 1 (1 mmol), hydrazine or phenyl hydrazine 2 (1 mmol), ethyl acetoacetate 3 (1 mmol), malononitrile 4 (1 mmol), water (5 mL), room temperature.b The yields are of pure products obtained after filtrated and recrystallization from ethanol.
A plausible reaction mechanism for this condensation is shown in Scheme 2. On the basis of the chemistry of pyranopyrazoles, it is reasonable to assume that pyrazolone derivative 6 was formed by the condensation reaction of hydrazine derivative 2 with ethyl acetoacetate 3.Then dicyanoalkene 8 was formed through the reaction base-catalyzed of aryl aldehyde 1 and malononitrile 4. The next step may involve Michael addition of the methylene group of pyrazolone 7 to an electron deficient carbon of dicyanoalkene 8, which gives an intermediate 9, leading to cyclic intermediate 10, followed by 10 is tautomerized to target pyranpyrazoles 5a-q.
The catalyst can be recovered by evaporation of solvent from filtrated solution after each run and reused.TLC showed that there was no starting materials or product in the filtered solution.All of the substrates were transferred to target products completely.Measuring the melting point of the solid residual after evaporation of the solvent, confirmed the presence of sodium benzoate in the filtrate.The recycled catalyst was applied in four consecutive runs of the same model reaction under the optimized conditions (1 th use: 90%, isolated yield, 2 th use: 89% isolated yield, 3 th use: 85% isolated yield, and 4 th use: 80% isolated yield).Decreasing the yield is probably related to slight reduction in the catalytic activity of sodium benzoate or decreasing of amount of recycled catalyst during the handling.

Conclusions
In conclusion, we have demonstrated a highly efficient method for the synthesis of pyranopyrazoles via four-component reaction of aromatic aldehydes, malononitrile, ethyl acetoacetate, and hydrazine hydrate or phenyl hydrazine using cheap and readily available low toxic organocatalyst sodium benzoate.The significant advantages of this procedure are operational simplicity, clean reaction, easy preparation and handling of the catalyst, increased safety, and environmental friendly reaction condition.

General
All the reagents and chemicals were obtained from commercial sources and used without further purification.Melting points were measured on a Buchi 510 melting point apparatus and are uncorrected.IR spectra were recorded on a Shimadzu FT-IR 8300 Spectrophotometer using KBr pellets technique. 1H NMR and 13 C NMR spectra were recorded at ambient temperature on a BRUKER AVANCE DRX-400 MHz spectrophotometer using dimethylsulfoxide (DMSO-d 6 ) as the solvent and TMS as an internal standard.The purity of synthesized compounds as well as a progress of the reactions was monitored by thin layer chromatography (TLC) on Merck pre-coated silica gel 60 F 254 aluminum sheets, visualized by UV light.